Hypoxia-Preconditioned Wharton's Jelly-Derived Mesenchymal Stem Cells Mitigate Stress-Induced Apoptosis and Ameliorate Human Islet Survival and Function in Direct Contact Coculture System.

Somayeh Keshtkar,Maryam Kaviani,Bita Geramizadeh,Mahdokht Hossein Aghdaei,Mohammad Hossein Ghahremani,Elaheh Esfandiari,Zahra Jabbarpour,Alireza Shamsaeefar,Fatemeh Sabet Sarvestani,Saman Nikeghbalian,Negar Azarpira,Mahmood S Choudhery

doi:10.1155/2020/8857457

Abstract

Protection of isolated pancreatic islets against hypoxic and oxidative damage-induced apoptosis is essential during a pretransplantation culture period. A beneficial approach to maintain viable and functional islets is the coculture period with mesenchymal stem cells (MSCs). Hypoxia preconditioning of MSCs (Hpc-MSCs) for a short time stimulates the expression and secretion of antiapoptotic, antioxidant, and prosurvival factors. The aim of the present study was to evaluate the survival and function of human islets cocultured with Hpc-MSCs. Wharton's jelly-derived MSCs were subjected to hypoxia (5% O2: Hpc) or normoxia (20% O2: Nc) for 24 hours and then cocultured with isolated human islets in direct and indirect systems. Assays of viability and apoptosis, along with the production of reactive oxygen species (ROS), hypoxia-inducible factor 1-alpha (HIF-1α), apoptotic pathway markers, and vascular endothelial growth factor (VEGF) in the islets, were performed. Insulin and C-peptide secretions as islet function were also evaluated. Hpc-MSCs and Nc-MSCs significantly reduced the ROS production and HIF-1α protein aggregation, as well as downregulation of proapoptotic proteins and upregulation of antiapoptotic marker along with increment of VEGF secretion in the cocultured islet. However, the Hpc-MSCs groups were better than Nc-MSCs cocultured islets. Hpc-MSCs in both direct and indirect coculture systems improved the islet survival, while promotion of function was only significant in the direct cocultured cells. Hpc potentiated the cytoprotective and insulinotropic effects of MSCs on human islets through reducing stressful markers, inhibiting apoptosis pathway, enhancing prosurvival factors, and promoting insulin secretion, especially in direct coculture system, suggesting the effective strategy to ameliorate the islet quality for better transplantation outcomes.

Highlights

Islet transplantation has emerged as a potential cell therapy to restore glucose homeostasis for selected type 1 diabetes patients that encounter severe hypoglycemic episodes
Hypoxia induces oxidative stress through reactive oxygen species (ROS) overproduction that leads to apoptosis during pre- and posttransplantation [3,4,5,6,7]
The aim of our study was to investigate whether HpcMSCs could reduce the stressful factors, inhibit mitochondrial apoptosis pathway, and improve human islet survival and function in direct and indirect coculture systems

Summary

Introduction

Islet transplantation has emerged as a potential cell therapy to restore glucose homeostasis for selected type 1 diabetes patients that encounter severe hypoglycemic episodes. The early initiator of islet destruction is hypoxia that induces apoptosis in the beta cells. Hypoxia induces oxidative stress through reactive oxygen species (ROS) overproduction that leads to apoptosis during pre- and posttransplantation [3,4,5,6,7]. Islet culturing is performed in order to prepare the graft recipient, quality control of the cells, and transportation to other centers [8, 9]. Studies have shown that isolated islets alone are unable to cope with hypoxia and oxidative stress during culture period. It is necessary to improve the culture period by clinically feasible methods to inhibit apoptosis and increase the quality of islets for better transplantation outcomes

Objectives

Methods

Findings

Conclusion